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Phase 3 Safety and Efficacy Study of ART-123 in Subjects With Severe Sepsis and Coagulopathy

Sponsor
Asahi Kasei Pharma America Corporation (Industry)
Overall Status
Completed
CT.gov ID
NCT01598831
Collaborator
(none)
816
Enrollment
161
Locations
2
Arms
76
Actual Duration (Months)
5.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate if ART-123 given to patients who have severe sepsis can decrease mortality.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Study is to evaluate if ART-123 given to patients who have severe sepsis complicated by at least one organ dysfunction and coagulopathy can decrease mortality.

Study Design

Study Type:
Interventional
Actual Enrollment :
816 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of ART-123 in Subjects With Severe Sepsis and Coagulopathy.
Actual Study Start Date :
Oct 29, 2012
Actual Primary Completion Date :
Apr 5, 2018
Actual Study Completion Date :
Feb 28, 2019

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: ART-123

Drug: ART-123
Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
Other Names:
  • human recombinant thrombomodulin
  • thrombomodulin alfa

    		•
    Placebo Comparator: Placebo

    Drug: Placebo
    Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days.

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With 28-Day All-cause Mortality [28 days]

      28-Day All-cause Mortality

    2. Number of Participants With On-Treatment Serious Major Bleeding Events [Through Study Day 28]

      On-treatment Serious Major Bleeding Events collected as Serious Adverse Events and defined as: any intracranial hemorrhage, any life-threatening bleeding, any bleeding event classified as serious by the Investigator (e.g., resulting in permanent morbidity), or any bleeding that required the administration of 1440 ml (typically 6 units) of packed red cells over two consecutive days. (Investigator assessment for seriousness criteria.)

    Secondary Outcome Measures

    1. Follow up All-cause Mortality at 3 Months [3 months]

      Follow up all-cause mortality at 3 months

    2. Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction [28 days]

      Resolution of organ dysfunction as measured through day 28 by shock free, ventilator free, dialysis free plus alive days.

    3. Number of Participants With Anti-drug Antibodies [18 months]

      Presence of Anti-drug antibodies up to 18 months

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Subject must be receiving treatment in an ICU, or in an acute care setting (e.g., ER, RR)

    • Clinical objective evidence of bacterial infection and a known site of infection.

    • Cardiovascular dysfunction or Respiratory Failure due to sepsis.

    • Coagulopathy characterized by an INR >1.40 without other known causes.

    Exclusion Criteria:

    • Subject or Authorized Representative is unable to provide informed consent.

    • Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of enrolling into the study.

    • Subject is of childbearing potential and does not have a negative pregnancy test.

    • Subject is < 18 years of age.

    • Subject has a known allergy to ART-123 or any components of the drug product.

    • Subject is unwilling to allow transfusion of blood or blood products.

    • Subject has an advance directive to withhold life-sustaining treatment.

    • Subject has had previous treatment with ART-123.

    • Body weight ≥ 175 kg.

    • Platelets < 30,000/ mm3 for any reason, PT prolongation or thrombocytopenia that is not due to sepsis.

    • Any surgery that is potentially hemorrhagic (e.g. intra-thoracic, intra-abdominal or non-traumatic orthopedic surgery of the femur or pelvis) that is completed within 12 hours prior to first dose of study drug, or ongoing impairment of hemostasis as a result of one of these procedures

    • History of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to consent.

    • Cerebral Vascular Accident (CVA) within 3 months prior to consent.

    • Any history of intracerebral arteriovenous malformation (AVM), cerebral aneurysm, or mass lesions of the central nervous system.

    • History of congenital bleeding diathesesor anatomical anomaly that predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia).

    • Significant gastrointestinal bleeding within 6 weeks prior to consent.

    • Subject is diagnosed with a known medical condition associated with a hypercoagulable state.

    • Child-Pugh score of 10-15 (Class C)

    • Portosystemic hypertension or known history of bleeding esophageal varices.

    • History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 6 months prior to consent.

    • Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture or gram stain consistent with bacterial infection.

    • Subjects with renal dysfunction defined as (a) Chronic renal failure requiring renal replacement therapy (RRT), or (b) Acute renal failure with onset of oliguria (urine output < 0.3 ml/kg/hr) > 48 hours prior to first dose of study drug whether receiving RRT or not

    • Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first does of study drug.

    • Life expectancy < 90 days.

    • Current use of any chemotherapy agent likely to cause myeloablation (severe or complete depletion of bone marrow).

    • Participation in another research study involving an investigational agent within 30 days prior to consent or projected study participation during the 28 days post study randomization.

    • Confirmed or suspected endocarditis

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mobile Alabama United States 36608
    2 Phoenix Arizona United States 85008
    3 Atlanta Georgia United States 30342
    4 Idaho Falls Idaho United States 83404
    5 Indianapolis Indiana United States 46202
    6 Hazard Kentucky United States 41701
    7 Louisville Kentucky United States 40202
    8 Detroit Receiving Hospital Detroit Michigan United States 48201
    9 Harper Hospital - Wayne State University School of Medicine Detroit Michigan United States 48201
    10 Sinai-Grace Hospital Detroit Michigan United States 48235
    11 Jackson Mississippi United States 39216
    12 Washington University in St. Louis Saint Louis Missouri United States 63110
    13 Butte Montana United States 59701
    14 Englewood New Jersey United States 07631
    15 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    16 Durham North Carolina United States 27710
    17 Columbus Ohio United States 43215
    18 Oklahoma City Oklahoma United States 73104
    19 Philadelphia Pennsylvania United States 19104
    20 Rapid City South Dakota United States 57701
    21 2 of 2 Houston Texas United States 77030
    22 Murray Utah United States 84107
    23 Hospital Italiano de Cordoba Cordoba Argentina X5004BAL
    24 Prince of Wales Hospital Randwick New South Wales Australia
    25 Royal Brisbane and Women's Hospital Herston Queensland Australia
    26 Princess Alexandra Hospital Woolloongabba Queensland Australia
    27 Royal Adelaide Hospital Adelaide South Australia Australia 5000
    28 Bendigo Hospital Bendigo Victoria Australia
    29 Monash Medical Centre Clayton Victoria Australia
    30 Dandenong Hospital Monash Health Dandenong Victoria Australia 3175
    31 Western Hospital Footscray Victoria Australia
    32 Austin Health Heidelberg Victoria Australia
    33 Sunshine Hospital Melbourne Victoria Australia 3021
    34 UZ Antwerpen Antwerpen Belgium
    35 Cliniques Du Sud-Luxerbourg (CSL), Hospital Saint Joseph Arlon Belgium
    36 CHU Brugmann Brussels Belgium
    37 Hopital Erasme Brussels Belgium
    38 Hopitaux Iris Sud Brussels Belgium
    39 UCL St. Luc Brussels Belgium
    40 UZ Brussel Brussels Belgium
    41 Centre Hospitalier de Dinant Dinant Belgium
    42 UZ Gent Gent Belgium
    43 Clinique Saint-Pierre Ottignies Belgium
    44 UCL Mont-Godinne Yvoir Belgium
    45 Santa Casa de Misericordia de Belo Horizonte Belo Horizonte MG Brazil
    46 Fundaçao Faculdade Regional de Medicina Sao Jose do Rio Preto Sao Jose do Rio Preto SP Brazil
    47 Hospital Pompéia Brasil Brazil 95010-005
    48 Anesthesiology and Intensive Care Clinic, University Multiprofile Hospital For Active Treatment "Sveti Georgi", Plovdiv Plovdiv Bulgaria
    49 Department of Anesthesiology and Intensive Care Multiprofile Hospital For Active Treatment "Tokuda Hospital Sofia", Sofia Sofia Bulgaria
    50 2 of 2 Calgary Alberta Canada T1Y 6J4
    51 Calgary Alberta Canada T2V 1PA
    52 Calgary Alberta Canada T3M 1M4
    53 Vancouver British Columbia Canada V5Z 1M9
    54 2 of 2 Vancouver British Columbia Canada V6Z 1Y6
    55 1 of 2 Victoria British Columbia Canada V8R-1J8
    56 Victoria British Columbia Canada V8R1J8
    57 Winnipeg Manitoba Canada
    58 Halifax Nova Scotia Canada
    59 London Ontario Canada N6A5W9
    60 1 of 2 Ottawa Ontario Canada KIH 8L6
    61 2 of 2 Ottawa Ontario Canada KIH 8L6
    62 Windsor Ontario Canada
    63 Montreal Quebec Canada
    64 Clinical Hospital Center Zagreb, Medical ICU Zagreb Croatia
    65 Clinical Hospital Dubrava, Department of Anesthesiology and resuscitation Zagreb Croatia
    66 University Hospital Center Zagreb, Department of Anesthesiology, Reanimatology and Intensive Care Medicine Zagreb Croatia
    67 University Hospital Brno, Department of Infectious Diseases Brno Czechia
    68 University Hospital Hradec Kralove, Department of Anaesthesiology, Resuscitation and Intensive Care Hradec Kralove Czechia
    69 University Hospital Kralovske Vinohrady, Department of Anesthesiology and Resuscitation Prague 10 Czechia
    70 General University Hospital in Prague, Department of Anaesthesiology, Resuscitation and Intensive Medicine Prague 2 Czechia
    71 Masaryk´s Hospital Ustni nad Labem, o.z., Department of Infectious Diseases Usti nad Labem Czechia
    72 Helsingin Yliopistollinen Keskussairaala (HYKS) (Helsinki University Central Hospital (HUCH)) Helsinki Finland
    73 Keski-Suomen Keskussairaala (Central Finland Central Hospital) Jyväskylä Finland
    74 Kuopion Yliopistollinen Sairaala (KYS) (Kuopio University Hospital) Kuopio Finland
    75 Tampereen Yliopistollinen Sairaala (Tampere University Hospital) (TAYS) - Keskussairaala (Central Hospital) Tampere Finland
    76 Archet 1 University Hospital of Nice Nice Cedex 3 France 23079
    77 Service de reanimation médicale. CHU Hotel Dieu Nantes Nantes Cedex 01 France 44093
    78 CHU D'Anger Angers Cedex 9 France
    79 CHU de Dijon, Hopital Bocage Central Dijon France 21000
    80 CH-Hôpital Albert Michallon Grenoble cedex 09 France
    81 Centre Hospitalier Départemental de Vendée-Les Oudairies La Roche-Sur-Yon cedex 9 France
    82 CHRU Lille-Pole Reanimation Lille France 59037
    83 CHU Limoges Limoges cedex France
    84 Centre Hospitalier Universitaire Nîmes Nîmes Cedex 9 France
    85 La Pitié Salpétrière, Paris Paris France 75013
    86 Hôpital COCHIN Paris France
    87 University Hospital of Bordeaux Pessac France 33600
    88 CH Lyon Sud Pierre-Bénite cedex France
    89 Nouvel hospital civil Strasbourg France 67000
    90 Hôpital Sainte Musse Toulon France
    91 CHU Tours, Hopital Bretonneau Tours France
    92 Universitätsklinikum der RWTH Aachen Aachen Germany 54074
    93 Helios Klinikum Erfurt Erfurt Germany
    94 Klinikum der Johann-Wolfgang Goethe-Universität Frankfurt am Main Germany
    95 Szent Imre Hospital, Anesthesiology and Intensive Care Unit Budapest Hungary 1115
    96 Maulana Azad Medical College and Associated L N Hospital New Delhi Delhi India
    97 Shalby Hospital Ahmedabad, Gujarat India 380015
    98 Shalby Ahmedabad Gujarat India
    99 Artemis Hospital Gurgaon Haryana India 122001
    100 Ruby Hall Clinic Pune Maharashtra India 411011
    101 Noble Hospital Pune Maharashtra India 411013
    102 King Edward Memorial Hospital & Research Centre Pune Maharashtra India
    103 Hi-tech Medical College & Hospital Bhubaneswar Odisha India
    104 Bharati Vidyapeeth Deemed University Medical College Bharti Hospital and Research Centre Pune Pune, Maharashtra India 411043
    105 St. Theresa Hospital Hyderabad Telangana State India 500018
    106 Mazumdar Shaw Medical Centre (Unit of Narayana Health) Bangalore India 560099
    107 KLES Dr. Prabhakar Kore Hospital & Medical Research Centre Belgaum India 590010
    108 JSS Hospital Mysore India 570004
    109 Care Hospital Nagpur India 440010
    110 Noble Hospital Pune India 411013
    111 Barzilai Medical Center Ashkelon Israel
    112 Rambam Medical Center Haifa Israel
    113 The Lady Davis Carmel Medical Center Haifa Israel
    114 Shaare Zedek Medical Center Jerusalem Israel
    115 Rabin Medical Center Petach Tikva Israel
    116 Kaplan Medical Center Rehovot Israel
    117 Korea University Anam Hospital Seongdu Korea, Republic of
    118 Asan Medical Center Seoul Korea, Republic of
    119 Samsung Medical Center [Pulmonology] Seoul Korea, Republic of
    120 Seoul National University Hospital Seoul Korea, Republic of
    121 Jeroen Bosch Ziekenhuis 's-Hertogenbosch Netherlands
    122 VUMC Amsterdam Netherlands
    123 Ziekenhuis Gelderse Vallei Ede Netherlands
    124 Medisch Spectrum Twente Enschede Netherlands
    125 University Medical Center Groningen Groningen Netherlands
    126 Medisch Centrum Leeuwarden Leeuwarden Netherlands
    127 UMC St. Radboud Nijmegen Netherlands
    128 Ikazia Ziekenhuis Rotterdam Netherlands
    129 Auckland District Health Board Auckland New Zealand
    130 Christchurch Hospital Christchurch New Zealand
    131 Hawkes Bay Regional Hospital Intensive Care Unit Omahu Road Hastings New Zealand
    132 Wellington District Health Board Newtown New Zealand 6021
    133 Hospital Nacional Almenara Yrigoyen - EsSALUD Lima Lima Province Peru
    134 Hospital Nacional FAP Lima Lima Province Peru
    135 Arkhangelsk Regional Clinical Hospital Arkhangelsk Russian Federation
    136 Volosevich City Clinical Hospital #1 Arkhangelsk Russian Federation
    137 City Clinical Hospital #3 n.a. M.A. Pogorbunskiy Kemerovo Russian Federation 650000
    138 Kuban State Medical University (Site Facility: Krasnodar Regional Clinical Hospital #2) Krasnodar Russian Federation
    139 Krasnoyarsk Regional Clinocal Hospital Krasnoyarsk Russian Federation 660022
    140 Vishnevsky Institute of Surgery Moscow Russian Federation
    141 St George City Hospital Saint Petersburg Russian Federation 194354
    142 City Hospital #40 Saint Petersburg Russian Federation
    143 City Hospital #4 Sochi Russian Federation 354057
    144 Aleksandrovskaya City Hospital St. Petersburg Russian Federation
    145 Mariinskaya City Hospital St. Petersburg Russian Federation
    146 Mechnikov North-Western State Medical University n.a. I.I. Mechnikov St. Petersburg Russian Federation
    147 Clinic for Infectious Diseases, Clinical Center Nis Nis Serbia
    148 Complexo Hospitalario Universitario A Coruña A Coruña Spain
    149 Hospital Universitario Mutua Terrassa Intensive Care Barcelona Spain
    150 Servicio de Medicina Intensiva Hospital Universitario Valle de Hebron Barcelona Spain
    151 Hospital Clínico San Carlos Madrid Spain
    152 Hospital de Sabadell Sabadell Spain
    153 Hospital Universitari de Tarragona Joan XXIII Tarragona Spain
    154 Chi Mei Medical Center Yong Kang Yongkang Tainan Taiwan
    155 Taichung Veterans General Hospital [Pulmonology] Taichung Taiwan
    156 National Taiwan University Hospital Taipei Taiwan
    157 Birmingham Heartlands Hospital Birmingham United Kingdom B9 5SS
    158 Hull Royal Infirmary Hull United Kingdom HU3 2JZ
    159 Royal Liverpool University Hospital Liverpool United Kingdom
    160 Manchester Royal Infirmary Manchester United Kingdom
    161 Derriford Hospital Plymouth United Kingdom

    Sponsors and Collaborators

    • Asahi Kasei Pharma America Corporation

    Investigators

    • Study Director: David Fineberg, M.D., Asahi Kasei Pharma America Corporation

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Asahi Kasei Pharma America Corporation
    ClinicalTrials.gov Identifier:
    NCT01598831
    Other Study ID Numbers:
    • 3-001
    First Posted:
    May 15, 2012
    Last Update Posted:
    Apr 21, 2020
    Last Verified:
    Mar 1, 2020
    Keywords provided by Asahi Kasei Pharma America Corporation
    sepsis
    Additional relevant MeSH terms:
    Sepsis
    Toxemia
    Hemostatic Disorders
    Blood Coagulation Disorders

    Study Results

    Participant Flow

    Recruitment Details This study was conducted at 319 sites in 27 countries; of these, 159 study sites (in 26 countries) assigned participants to study drug treatment. First participant was randomized on Oct 29, 2012 and the last participant was randomized on Mar 8, 2018. Last participant completed long term follow-up (survival only) on Feb 28, 2019.
    Pre-assignment Detail Of 946 consented participants, 816 randomized to study treatment, 800 received at least 1 dose of study treatment.
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    Period Title: Overall Study
    STARTED 402 414
    Received at Least 1 Dose Study Treatment 395 405
    COMPLETED 283 278
    NOT COMPLETED 119 136

    Baseline Characteristics

    Arm/Group Title ART-123 Placebo Total
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Total of all reporting groups
    Overall Participants 395 405 800
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    231
    58.5%
    231
    57%
    462
    57.8%
    >=65 years
    164
    41.5%
    174
    43%
    338
    42.3%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    61.0
    (15.87)
    60.5
    (15.94)
    60.7
    (15.89)
    Sex: Female, Male (Count of Participants)
    Female
    179
    45.3%
    184
    45.4%
    363
    45.4%
    Male
    216
    54.7%
    221
    54.6%
    437
    54.6%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    20
    5.1%
    22
    5.4%
    42
    5.3%
    Not Hispanic or Latino
    290
    73.4%
    285
    70.4%
    575
    71.9%
    Unknown or Not Reported
    85
    21.5%
    98
    24.2%
    183
    22.9%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    5
    1.3%
    8
    2%
    13
    1.6%
    Asian
    56
    14.2%
    58
    14.3%
    114
    14.3%
    Native Hawaiian or Other Pacific Islander
    1
    0.3%
    2
    0.5%
    3
    0.4%
    Black or African American
    14
    3.5%
    20
    4.9%
    34
    4.3%
    White
    312
    79%
    308
    76%
    620
    77.5%
    More than one race
    7
    1.8%
    9
    2.2%
    16
    2%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    34
    8.6%
    37
    9.1%
    71
    8.9%
    Czechia
    10
    2.5%
    11
    2.7%
    21
    2.6%
    Russia
    54
    13.7%
    57
    14.1%
    111
    13.9%
    Greece
    0
    0%
    1
    0.2%
    1
    0.1%
    Netherlands
    22
    5.6%
    27
    6.7%
    49
    6.1%
    South Korea
    4
    1%
    2
    0.5%
    6
    0.8%
    Brazil
    11
    2.8%
    8
    2%
    19
    2.4%
    Bulgaria
    1
    0.3%
    1
    0.2%
    2
    0.3%
    France
    75
    19%
    74
    18.3%
    149
    18.6%
    Serbia
    1
    0.3%
    1
    0.2%
    2
    0.3%
    Croatia
    6
    1.5%
    5
    1.2%
    11
    1.4%
    Colombia
    2
    0.5%
    0
    0%
    2
    0.3%
    Argentina
    1
    0.3%
    0
    0%
    1
    0.1%
    Hungary
    0
    0%
    1
    0.2%
    1
    0.1%
    United Kingdom
    6
    1.5%
    4
    1%
    10
    1.3%
    India
    41
    10.4%
    44
    10.9%
    85
    10.6%
    Spain
    9
    2.3%
    11
    2.7%
    20
    2.5%
    New Zealand
    6
    1.5%
    5
    1.2%
    11
    1.4%
    Canada
    22
    5.6%
    24
    5.9%
    46
    5.8%
    Belgium
    34
    8.6%
    34
    8.4%
    68
    8.5%
    Finland
    18
    4.6%
    19
    4.7%
    37
    4.6%
    Taiwan
    4
    1%
    4
    1%
    8
    1%
    Israel
    9
    2.3%
    10
    2.5%
    19
    2.4%
    Australia
    19
    4.8%
    19
    4.7%
    38
    4.8%
    Peru
    3
    0.8%
    2
    0.5%
    5
    0.6%
    Germany
    3
    0.8%
    4
    1%
    7
    0.9%
    Height (cm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm]
    167.39
    (8.729)
    168.02
    (9.619)
    167.71
    (9.190)
    Weight (kg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg]
    75.01
    (19.131)
    75.74
    (19.266)
    75.38
    (19.191)
    APACHE II (mean, SD) (Total Score) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Total Score]
    22.34
    (8.071)
    22.10
    (8.025)
    22.22
    (8.043)
    Arterial Lactate >55mg/dl (mean, SD) (Count of Participants)
    Count of Participants [Participants]
    53
    13.4%
    52
    12.8%
    105
    13.1%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With 28-Day All-cause Mortality
    Description 28-Day All-cause Mortality
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set - All randomized and dosed subjects.
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    Measure Participants 395 405
    Count of Participants [Participants]
    106
    26.8%
    119
    29.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection ART-123, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.318
    Comments The threshold for statistical significance was a two sided 5%
    Method Cochran-Mantel-Haenszel
    Comments CMH test controlled for the stratification factor.
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -2.55
    Confidence Interval (2-Sided) 95%
    -3.68 to 8.77
    Parameter Dispersion Type:
    Value:
    Estimation Comments Rates by Arm are 26.8% for ART-123 and 29.4% for Placebo
    Other Statistical Analysis In a post hoc sensitivity analysis for the primary outcome that accounted for pooled site as a random effect, the adjusted 28-day all-cause mortality rate was 24.8%in the rhsTM group vs 27.5%in the placebo group (P = .31).
    2. Primary Outcome
    Title Number of Participants With On-Treatment Serious Major Bleeding Events
    Description On-treatment Serious Major Bleeding Events collected as Serious Adverse Events and defined as: any intracranial hemorrhage, any life-threatening bleeding, any bleeding event classified as serious by the Investigator (e.g., resulting in permanent morbidity), or any bleeding that required the administration of 1440 ml (typically 6 units) of packed red cells over two consecutive days. (Investigator assessment for seriousness criteria.)
    Time Frame Through Study Day 28

    Outcome Measure Data

    Analysis Population Description
    Safety population: all subjects who received at least 1 dose of study drug (analyzed according to study drug received; any subjects receiving both ART-123 and placebo were to be included in the ART-123 group)
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    Measure Participants 396 404
    Count of Participants [Participants]
    23
    5.8%
    16
    4%
    3. Secondary Outcome
    Title Follow up All-cause Mortality at 3 Months
    Description Follow up all-cause mortality at 3 months
    Time Frame 3 months

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set - All randomized and dosed subjects.
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    Measure Participants 395 405
    Count of Participants [Participants]
    126
    31.9%
    136
    33.6%
    4. Secondary Outcome
    Title Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction
    Description Resolution of organ dysfunction as measured through day 28 by shock free, ventilator free, dialysis free plus alive days.
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set - All randomized and dosed subjects.
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    Measure Participants 395 405
    Shock-free and alive
    17.6
    (10.50)
    17.6
    (10.56)
    Ventilation-free and alive
    15.8
    (11.75)
    14.5
    (11.90)
    Dialysis-free and alive
    20.2
    (11.05)
    19.6
    (11.21)
    5. Secondary Outcome
    Title Number of Participants With Anti-drug Antibodies
    Description Presence of Anti-drug antibodies up to 18 months
    Time Frame 18 months

    Outcome Measure Data

    Analysis Population Description
    Safety population: all subjects who received at least 1 dose of study drug (analyzed according to study drug received; any subjects receiving both ART-123 and placebo were to be included in the ART-123 group)
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    Measure Participants 396 404
    Count of Participants [Participants]
    0
    0%
    0
    0%
    6. Post-Hoc Outcome
    Title Day 28 Mortality in Subjects With INR > 1.4 at Baseline and PLT > 30K at Baseline
    Description Post-Hoc analysis of Day 28 Mortality in Subjects with INR > 1.4 at Baseline and PLT > 30K at Baseline
    Time Frame Day 28

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set - All randomized and dosed subjects.
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    Measure Participants 307 327
    Count of Participants [Participants]
    82
    20.8%
    105
    25.9%

    Adverse Events

    Time Frame Adverse events were collected between randomization and through Day 28 only. SAEs were collected from the time of authorization to randomize the participants until Day 28. All-cause mortality were collected as Fatal SAEs between randomization and Day 28 (End of Study) and as survival follow-up from Day 28 until 12 months.
    Adverse Event Reporting Description AEs were analyzed using a safety population that includes all subjects who received at least 1 dose of study drug (analyzed according to study drug received; any subjects receiving both ART-123 and placebo were to be included in the ART-123 group). Treatment Emergent Serious Adverse Events (TESAE) were analyzed by System Organ Class and Preferred Term. A treatment-emergent adverse event (TEAE) is defined as any AE following exposure to study treatment.
    Arm/Group Title ART-123 Placebo
    Arm/Group Description ART-123 (human recombinant thrombomodulin, thrombomodulin alfa) Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days Placebo Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days
    All Cause Mortality
    ART-123 Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 141/395 (35.7%) 148/405 (36.5%)
    Serious Adverse Events
    ART-123 Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 206/396 (52%) 202/404 (50%)
    Blood and lymphatic system disorders
    Thrombocytopenia 10/396 (2.5%) 12/404 (3%)
    Anaemia 5/396 (1.3%) 7/404 (1.7%)
    Disseminated intravascular coagulation 1/396 (0.3%) 2/404 (0.5%)
    Coagulopathy 0/396 (0%) 1/404 (0.2%)
    Eosinophilia 1/396 (0.3%) 0/404 (0%)
    Haemolysis 0/396 (0%) 1/404 (0.2%)
    Leukocytosis 0/396 (0%) 1/404 (0.2%)
    Pancytopenia 0/396 (0%) 1/404 (0.2%)
    Cardiac disorders
    Cardiac arrest 10/396 (2.5%) 11/404 (2.7%)
    Atrial fibrillation 6/396 (1.5%) 5/404 (1.2%)
    Bradycardia 4/396 (1%) 2/404 (0.5%)
    Cardiac failure acute 4/396 (1%) 2/404 (0.5%)
    Cardiopulmonary failure 2/396 (0.5%) 3/404 (0.7%)
    Myocardial infarction 1/396 (0.3%) 3/404 (0.7%)
    Cardio-respiratory arrest 3/396 (0.8%) 0/404 (0%)
    Ventricular tachycardia 1/396 (0.3%) 2/404 (0.5%)
    Arrhythmia 2/396 (0.5%) 0/404 (0%)
    Cardiac failure 1/396 (0.3%) 1/404 (0.2%)
    Cardiogenic shock 1/396 (0.3%) 1/404 (0.2%)
    Supraventricular tachycardia 1/396 (0.3%) 1/404 (0.2%)
    Acute coronary syndrome 0/396 (0%) 1/404 (0.2%)
    Acute myocardial infarction 1/396 (0.3%) 0/404 (0%)
    Aortic valve incompetence 0/396 (0%) 1/404 (0.2%)
    Atrial flutter 1/396 (0.3%) 0/404 (0%)
    Atrial tachycardia 1/396 (0.3%) 0/404 (0%)
    Cardiac failure congestive 0/396 (0%) 1/404 (0.2%)
    Congestive cardiomyopathy 1/396 (0.3%) 0/404 (0%)
    Coronary artery stenosis 0/396 (0%) 1/404 (0.2%)
    Intracardiac thrombus 1/396 (0.3%) 0/404 (0%)
    Myocarditis 0/396 (0%) 1/404 (0.2%)
    Pericarditis 0/396 (0%) 1/404 (0.2%)
    Pulseless electrical activity 0/396 (0%) 1/404 (0.2%)
    Ear and labyrinth disorders
    Deafness bilateral 0/396 (0%) 1/404 (0.2%)
    Endocrine disorders
    Adrenal haemorrhage 1/396 (0.3%) 0/404 (0%)
    Gastrointestinal disorders
    Intestinal ischaemia 7/396 (1.8%) 6/404 (1.5%)
    Gastrointestinal haemorrhage 2/396 (0.5%) 5/404 (1.2%)
    Gastrointestinal necrosis 3/396 (0.8%) 2/404 (0.5%)
    Intestinal perforation 3/396 (0.8%) 1/404 (0.2%)
    Large intestine perforation 1/396 (0.3%) 2/404 (0.5%)
    Abdominal pain 2/396 (0.5%) 0/404 (0%)
    Abdominal hernia 0/396 (0%) 1/404 (0.2%)
    Constipation 1/396 (0.3%) 0/404 (0%)
    Diarrhoea 1/396 (0.3%) 0/404 (0%)
    Fistula of small intestine 0/396 (0%) 1/404 (0.2%)
    Gastrointestinal disorder 0/396 (0%) 1/404 (0.2%)
    Gastrointestinal perforation 1/396 (0.3%) 0/404 (0%)
    Gastrointestinal ulcer haemorrhage 1/396 (0.3%) 0/404 (0%)
    Gastrointestinal wall abnormal 0/396 (0%) 1/404 (0.2%)
    Hernial eventration 1/396 (0.3%) 0/404 (0%)
    Intestinal haemorrhage 1/396 (0.3%) 0/404 (0%)
    Intra-abdominal haematoma 1/396 (0.3%) 0/404 (0%)
    Intra-abdominal haemorrhage 1/396 (0.3%) 0/404 (0%)
    Mesenteric artery thrombosis 0/396 (0%) 1/404 (0.2%)
    Mesenteric haemorrhage 1/396 (0.3%) 0/404 (0%)
    Mesenteric vein thrombosis 0/396 (0%) 1/404 (0.2%)
    Mouth haemorrhage 1/396 (0.3%) 0/404 (0%)
    Oesophageal haemorrhage 1/396 (0.3%) 0/404 (0%)
    Pancreatic haemorrhage 1/396 (0.3%) 0/404 (0%)
    Rectal haemorrhage 0/396 (0%) 1/404 (0.2%)
    Retroperitoneal haematoma 1/396 (0.3%) 0/404 (0%)
    Retroperitoneal haemorrhage 1/396 (0.3%) 0/404 (0%)
    Thrombosis mesenteric vessel 1/396 (0.3%) 0/404 (0%)
    Upper gastrointestinal haemorrhage 0/396 (0%) 1/404 (0.2%)
    General disorders
    Multiple organ dysfunction syndrome 24/396 (6.1%) 28/404 (6.9%)
    Death 0/396 (0%) 2/404 (0.5%)
    Pyrexia 2/396 (0.5%) 0/404 (0%)
    Catheter site haematoma 1/396 (0.3%) 0/404 (0%)
    Catheter site haemorrhage 0/396 (0%) 1/404 (0.2%)
    Organ failure 0/396 (0%) 1/404 (0.2%)
    Hepatobiliary disorders
    Hepatic function abnormal 3/396 (0.8%) 2/404 (0.5%)
    Ischaemic hepatitis 1/396 (0.3%) 3/404 (0.7%)
    Hepatocellular injury 2/396 (0.5%) 1/404 (0.2%)
    Acute hepatic failure 1/396 (0.3%) 1/404 (0.2%)
    Cholecystitis acute 0/396 (0%) 1/404 (0.2%)
    Hepatic failure 1/396 (0.3%) 0/404 (0%)
    Hepatic necrosis 1/396 (0.3%) 0/404 (0%)
    Infections and infestations
    Septic shock 28/396 (7.1%) 30/404 (7.4%)
    Sepsis 8/396 (2%) 11/404 (2.7%)
    Pneumonia 8/396 (2%) 10/404 (2.5%)
    Peritonitis 3/396 (0.8%) 3/404 (0.7%)
    Gangrene 3/396 (0.8%) 2/404 (0.5%)
    Necrotising fasciitis 1/396 (0.3%) 3/404 (0.7%)
    Endocarditis 2/396 (0.5%) 1/404 (0.2%)
    Endocarditis bacterial 1/396 (0.3%) 1/404 (0.2%)
    Abdominal sepsis 0/396 (0%) 1/404 (0.2%)
    Abdominal wall abscess 1/396 (0.3%) 0/404 (0%)
    Abscess limb 1/396 (0.3%) 0/404 (0%)
    Bacteraemia 0/396 (0%) 1/404 (0.2%)
    Catheter site infection 1/396 (0.3%) 0/404 (0%)
    Cellulitis 0/396 (0%) 1/404 (0.2%)
    Cellulitis gangrenous 0/396 (0%) 1/404 (0.2%)
    Fungal sepsis 1/396 (0.3%) 0/404 (0%)
    Haematoma infection 1/396 (0.3%) 0/404 (0%)
    Hepatic infection 1/396 (0.3%) 0/404 (0%)
    Herpes simplex pneumonia 0/396 (0%) 1/404 (0.2%)
    Infection 0/396 (0%) 1/404 (0.2%)
    Infectious pleural effusion 0/396 (0%) 1/404 (0.2%)
    Infective aneurysm 1/396 (0.3%) 0/404 (0%)
    Influenza 0/396 (0%) 1/404 (0.2%)
    Liver abscess 1/396 (0.3%) 0/404 (0%)
    Lung infection 1/396 (0.3%) 0/404 (0%)
    Pneumococcal sepsis 1/396 (0.3%) 0/404 (0%)
    Pneumonia fungal 1/396 (0.3%) 0/404 (0%)
    Pneumonia staphylococcal 0/396 (0%) 1/404 (0.2%)
    Postoperative wound infection 0/396 (0%) 1/404 (0.2%)
    Renal abscess 1/396 (0.3%) 0/404 (0%)
    Septic embolus 0/396 (0%) 1/404 (0.2%)
    Staphylococcal infection 0/396 (0%) 1/404 (0.2%)
    Staphylococcal sepsis 1/396 (0.3%) 0/404 (0%)
    Systemic candida 0/396 (0%) 1/404 (0.2%)
    Tracheobronchitis 1/396 (0.3%) 0/404 (0%)
    Varicella zoster pneumonia 1/396 (0.3%) 0/404 (0%)
    Injury, poisoning and procedural complications
    Post procedural haemorrhage 6/396 (1.5%) 2/404 (0.5%)
    Overdose 1/396 (0.3%) 4/404 (1%)
    Anastomotic leak 1/396 (0.3%) 2/404 (0.5%)
    Wound haemorrhage 1/396 (0.3%) 2/404 (0.5%)
    Subdural haematoma 1/396 (0.3%) 1/404 (0.2%)
    Wound dehiscence 1/396 (0.3%) 1/404 (0.2%)
    Abdominal wound dehiscence 0/396 (0%) 1/404 (0.2%)
    Ankle fracture 1/396 (0.3%) 0/404 (0%)
    Chemical peritonitis 0/396 (0%) 1/404 (0.2%)
    Endotracheal intubation complication 0/396 (0%) 1/404 (0.2%)
    Femur fracture 1/396 (0.3%) 0/404 (0%)
    Gastrointestinal anastomotic leak 0/396 (0%) 1/404 (0.2%)
    Intestinal anastomosis complication 1/396 (0.3%) 0/404 (0%)
    Post procedural haematoma 1/396 (0.3%) 0/404 (0%)
    Procedural haemorrhage 1/396 (0.3%) 0/404 (0%)
    Investigations
    Platelet count decreased 2/396 (0.5%) 0/404 (0%)
    Coma scale abnormal 1/396 (0.3%) 0/404 (0%)
    Glutamate dehydrogenase increased 1/396 (0.3%) 0/404 (0%)
    Haemoglobin decreased 0/396 (0%) 1/404 (0.2%)
    Hepatic enzyme abnormal 1/396 (0.3%) 0/404 (0%)
    Hepatic enzyme increased 1/396 (0.3%) 0/404 (0%)
    International normalised ratio abnormal 0/396 (0%) 1/404 (0.2%)
    Oxygen saturation decreased 1/396 (0.3%) 0/404 (0%)
    Metabolism and nutrition disorders
    Diabetic ketoacidosis 1/396 (0.3%) 0/404 (0%)
    Electrolyte imbalance 1/396 (0.3%) 0/404 (0%)
    Hyperkalaemia 1/396 (0.3%) 0/404 (0%)
    Hypernatraemia 0/396 (0%) 1/404 (0.2%)
    Hypocalcaemia 0/396 (0%) 1/404 (0.2%)
    Hypoglycaemia 1/396 (0.3%) 0/404 (0%)
    Hypovolaemia 0/396 (0%) 1/404 (0.2%)
    Malnutrition 0/396 (0%) 1/404 (0.2%)
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage 2/396 (0.5%) 0/404 (0%)
    Compartment syndrome 0/396 (0%) 1/404 (0.2%)
    Rhabdomyolysis 0/396 (0%) 1/404 (0.2%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma 0/396 (0%) 1/404 (0.2%)
    Prostate cancer 1/396 (0.3%) 0/404 (0%)
    Tumour haemorrhage 0/396 (0%) 1/404 (0.2%)
    Nervous system disorders
    Ischaemic stroke 4/396 (1%) 0/404 (0%)
    Cerebral infarction 1/396 (0.3%) 2/404 (0.5%)
    Embolic cerebral infarction 2/396 (0.5%) 1/404 (0.2%)
    Cerebral haemorrhage 1/396 (0.3%) 1/404 (0.2%)
    Cerebrovascular accident 1/396 (0.3%) 1/404 (0.2%)
    Epilepsy 1/396 (0.3%) 1/404 (0.2%)
    Intensive care unit acquired weakness 0/396 (0%) 2/404 (0.5%)
    Brain hypoxia 0/396 (0%) 1/404 (0.2%)
    Brain injury 1/396 (0.3%) 0/404 (0%)
    Brain oedema 0/396 (0%) 1/404 (0.2%)
    Brain stem ischaemia 0/396 (0%) 1/404 (0.2%)
    Cerebral atrophy 1/396 (0.3%) 0/404 (0%)
    Cerebral haematoma 1/396 (0.3%) 0/404 (0%)
    Facial paralysis 0/396 (0%) 1/404 (0.2%)
    Haemorrhage intracranial 1/396 (0.3%) 0/404 (0%)
    Hypercapnic coma 1/396 (0.3%) 0/404 (0%)
    Hypoxic-ischaemic encephalopathy 0/396 (0%) 1/404 (0.2%)
    Paraplegia 0/396 (0%) 1/404 (0.2%)
    Polyneuropathy 1/396 (0.3%) 0/404 (0%)
    Posterior reversible encephalopathy syndrome 1/396 (0.3%) 0/404 (0%)
    Seizure 1/396 (0.3%) 0/404 (0%)
    Syncope 1/396 (0.3%) 0/404 (0%)
    Psychiatric disorders
    Delirium 1/396 (0.3%) 0/404 (0%)
    Renal and urinary disorders
    Acute kidney injury 14/396 (3.5%) 10/404 (2.5%)
    Renal failure 3/396 (0.8%) 1/404 (0.2%)
    Renal impairment 2/396 (0.5%) 1/404 (0.2%)
    Anuria 1/396 (0.3%) 1/404 (0.2%)
    Haematuria 1/396 (0.3%) 0/404 (0%)
    Renal ischaemia 1/396 (0.3%) 0/404 (0%)
    Renal tubular necrosis 0/396 (0%) 1/404 (0.2%)
    Urinary bladder haemorrhage 0/396 (0%) 1/404 (0.2%)
    Reproductive system and breast disorders
    Pelvic fluid collection 0/396 (0%) 1/404 (0.2%)
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure 11/396 (2.8%) 14/404 (3.5%)
    Acute respiratory distress syndrome 8/396 (2%) 9/404 (2.2%)
    Acute respiratory failure 5/396 (1.3%) 3/404 (0.7%)
    Pneumothorax 1/396 (0.3%) 4/404 (1%)
    Pulmonary embolism 2/396 (0.5%) 3/404 (0.7%)
    Haemoptysis 2/396 (0.5%) 2/404 (0.5%)
    Hypoxia 2/396 (0.5%) 1/404 (0.2%)
    Epistaxis 2/396 (0.5%) 0/404 (0%)
    Hypercapnia 1/396 (0.3%) 1/404 (0.2%)
    Pleural effusion 1/396 (0.3%) 1/404 (0.2%)
    Pleurisy 1/396 (0.3%) 1/404 (0.2%)
    Respiratory distress 0/396 (0%) 2/404 (0.5%)
    Acute pulmonary oedema 0/396 (0%) 1/404 (0.2%)
    Aspiration 0/396 (0%) 1/404 (0.2%)
    Atelectasis 1/396 (0.3%) 0/404 (0%)
    Diaphragm muscle weakness 1/396 (0.3%) 0/404 (0%)
    Haemothorax 0/396 (0%) 1/404 (0.2%)
    Pneumomediastinum 1/396 (0.3%) 0/404 (0%)
    Pneumonia aspiration 1/396 (0.3%) 0/404 (0%)
    Pulmonary haematoma 1/396 (0.3%) 0/404 (0%)
    Pulmonary oedema 0/396 (0%) 1/404 (0.2%)
    Respiratory arrest 0/396 (0%) 1/404 (0.2%)
    Respiratory tract oedema 1/396 (0.3%) 0/404 (0%)
    Stridor 0/396 (0%) 1/404 (0.2%)
    Vascular disorders
    Extremity necrosis 6/396 (1.5%) 6/404 (1.5%)
    Shock 4/396 (1%) 7/404 (1.7%)
    Deep vein thrombosis 2/396 (0.5%) 4/404 (1%)
    Shock haemorrhagic 6/396 (1.5%) 0/404 (0%)
    Hypotension 1/396 (0.3%) 2/404 (0.5%)
    Arterial occlusive disease 2/396 (0.5%) 0/404 (0%)
    Peripheral ischaemia 1/396 (0.3%) 1/404 (0.2%)
    Aortic thrombosis 1/396 (0.3%) 0/404 (0%)
    Arterial haemorrhage 0/396 (0%) 1/404 (0.2%)
    Arterial thrombosis 1/396 (0.3%) 0/404 (0%)
    Circulatory collapse 0/396 (0%) 1/404 (0.2%)
    Haemorrhage 1/396 (0.3%) 0/404 (0%)
    Peripheral coldness 0/396 (0%) 1/404 (0.2%)
    Venous thrombosis limb 0/396 (0%) 1/404 (0.2%)
    Other (Not Including Serious) Adverse Events
    ART-123 Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 271/396 (68.4%) 264/404 (65.3%)
    Blood and lymphatic system disorders
    Anaemia 99/396 (25%) 78/404 (19.3%)
    Thrombocytopenia 40/396 (10.1%) 51/404 (12.6%)
    Cardiac disorders
    Atrial fibrillation 51/396 (12.9%) 52/404 (12.9%)
    Gastrointestinal disorders
    Constipation 37/396 (9.3%) 37/404 (9.2%)
    Diarrhoea 31/396 (7.8%) 36/404 (8.9%)
    Nausea 31/396 (7.8%) 18/404 (4.5%)
    General disorders
    Pyrexia 39/396 (9.8%) 33/404 (8.2%)
    Oedema peripheral 20/396 (5.1%) 17/404 (4.2%)
    Infections and infestations
    Pneumonia 21/396 (5.3%) 22/404 (5.4%)
    Metabolism and nutrition disorders
    Hypokalaemia 83/396 (21%) 69/404 (17.1%)
    Hypophosphataemia 46/396 (11.6%) 39/404 (9.7%)
    Hyperglycaemia 37/396 (9.3%) 34/404 (8.4%)
    Hypoglycaemia 25/396 (6.3%) 31/404 (7.7%)
    Hyperkalaemia 25/396 (6.3%) 20/404 (5%)
    Hypomagnesaemia 25/396 (6.3%) 19/404 (4.7%)
    Hypernatraemia 21/396 (5.3%) 22/404 (5.4%)
    Fluid overload 21/396 (5.3%) 16/404 (4%)
    Hypocalcaemia 21/396 (5.3%) 11/404 (2.7%)
    Psychiatric disorders
    Delirium 31/396 (7.8%) 21/404 (5.2%)
    Insomnia 20/396 (5.1%) 21/404 (5.2%)
    Renal and urinary disorders
    Acute kidney injury 28/396 (7.1%) 13/404 (3.2%)
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 27/396 (6.8%) 31/404 (7.7%)
    Vascular disorders
    Hypertension 23/396 (5.8%) 25/404 (6.2%)
    Hypotension 23/396 (5.8%) 24/404 (5.9%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Director of Clinical Operations
    Organization Asahi Kasei Pharma America Corp.
    Phone (781) 419-1919
    Email pallton@akpamerica.com
    Responsible Party:
    Asahi Kasei Pharma America Corporation
    ClinicalTrials.gov Identifier:
    NCT01598831
    Other Study ID Numbers:
    • 3-001
    First Posted:
    May 15, 2012
    Last Update Posted:
    Apr 21, 2020
    Last Verified:
    Mar 1, 2020